Tiny RNA Molecules Control Breast Cancer's Spread

Finding could lead to better prognosis, treatments, researchers say

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WEDNESDAY, Jan. 9, 2008 (HealthDay News) -- Researchers have zeroed in on a handful of tiny ribonucleic acid (RNA) molecules that seem to control whether or not breast cancer travels to the lung and bone.

These "microRNAs" essentially serve as brakes on the proliferation of cancer. When they are missing, that allows the disease to spread freely. When they are restored, however, the cancer cells lose some of their ability to metastasize, the Memorial Sloan-Kettering Cancer Center scientists report.

The work has implications both for predicting which cancers are aggressive and establishing new targets for drug therapy down the line.

"It's very interesting early research and may avail one day to discovering agents to suppress the growth of metastases," said Dr. Jay Brooks, chairman of hematology/oncology at Ochsner Health System in Baton Rouge, La. "It's very fine research."

The findings could also help individualize cancer therapies.

"One of the fundamental lessons which should be reinforced from this study is that breast cancer is not one disease. It is clearly a family of diseases and identifying mechanisms that turn on or turn off genes in one cancer helps us with what I would call class prediction," added Dr. Patrick Borgen, director of the Brooklyn Breast Cancer Project at Maimonides Cancer Center in New York City. "This is important, because it gives us another box to classify breast cancers in. The primary reason that more progress has not been made is that we've used a one-size-fits-all treatment paradigm for breast cancer."

"Researchers have opened up a whole new window on ways to look at subsetting breast cancers. That holds short-term possibilities to go back and look for a predictor of prognosis or predictor of response to therapy based on these small RNA molecules. That really is a very tangible short-term goal," Borgen added. "That, in and of itself, would be exciting enough, but unlike most prognostic factors that we identify, this is one [that] represents a potential target for intervention. I think this is really exciting. I think this is the real deal."

If patients with more ominous cancers can be identified, doctors can then focus on administering more aggressive therapies from the start.

Most deaths from cancer occur after a tumor has metastasized or spread to other parts of the body.

"Metastasis is the overwhelming cause of death of patients that we see from cancer," confirmed study author Dr. Sohail F. Tavazoie, a postdoctoral fellow in the oncology-hematology fellowship program at Sloan-Kettering, in New York City.

But why are some cancers prone to spread while others are not?

Part of the answer lies in microRNAs, which subdue the activity of sets of genes linked to metastasis.

DNA is made up two strands (a double helix) of "letters" that contain all the information needed to create cells. RNAs are single-stranded copies of segments of the DNA, Tavazoie explained. While many RNAs are translated into proteins, others (including microRNAs) have the power to shut off genes.

The microRNAs appear to act as master "supervisor" or regulator of these sets of genes.

Tavazoie hypothesized that some of these microRNAs are missing in more dangerous cancers. "The brakes are lifted, so a group of genes could actually be activated," he explained.

Tavazoie and his colleagues, who published their findings in the Jan. 10 issue of Nature, investigated how microRNAs might play a role in controlling the expression of genes that in turn control metastases.

First, they compared microRNAs produced by metastatic human cancerous cells with those produced by non-metastatic cancer cells in the laboratory.

"We saw that the highly metastatic cancer cells had lost some of these small RNA molecules," Tavazoie said.

Could some of these molecules be the so-called supervisors of other genes involved in cancer becoming lethal?

In fact, when three of eight microRNAs identified were put back into aggressive cells, those cells backed down, becoming less likely to spread. These experiments were done in mice programmed with human cancer cells.

The researchers then took the project a step further, predicting that women with breast cancer who had lost these small RNA molecules would be more likely to have an aggressive form of cancer.

"Indeed, when I looked at two of the microRNAs, women who had lost either of them had a significantly higher risk for having the cancers come back," Tavazoie said. "This supported the hypothesis that these small RNA molecules could be playing an important role in regulating the spread of cancers."

Tavazoie then identified six genes or "players" that one of these "supervisors" regulated. He took out two of the genes in lab mice and watched the cancer become more aggressive.

"The 'supervisors' put the brakes on the 'players,' so when you take out the players, the cells can't spread any more," Tavazoie explained.

When he analyzed genes from more than 300 cancer patients, he found that women with higher levels of the six genes had a greater chance of having the cancer move to the lung and bone.

"The story suggests that these small RNAs seem to play an important supervisory or regulatory role in putting a brake on some of these genes," Tavazoie said. "In women whose cancers have lost this brake, it seems that they're more likely for the cancer to spread."